Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and its mortality rate is expected to climb steadily over the next 20 years. In the US, this condition causes over 700,000 hospitalizations per year and leads to $20-26 billion in annual health care expenditures. There is currently no cure for COPD, and the limited therapies currently available mainly reduce symptoms rather than reverse the disease or prevent its progression. While the role cigarette smoke plays in COPD is undisputed, the mechanism by which inhaled smoke contributes to disease pathogenesis remains unclear. One of the major barriers to the development of new approaches to diagnose and manage COPD is the clinical heterogeneity displayed by COPD patients. While COPD has been defined as a disease state characterized by airflow limitation that is not fully reversible, there are diverse clinical, radiographic, and pathologic findings that likely reflect different underlying molecular and pathogenic disease mechanisms. Cigarette smoke causes an airway-wide "field of injury", and gene expression in bronchial airway cells of smokers obtained by brushings at bronchoscopy reflects both this injury and subsequent disease-specific processes. This proposal examines the hypothesis that determining the gene-expression profile of airway epithelial cells in individuals with and without COPD will provide insights into the molecular pathogenesis of COPD and specific COPD-related traits, including degree of airflow obstruction, emphysema, small airways disease, and the rate of disease progression. Alterations in airway gene and microRNA expression will be used to define the underlying pathways that are perturbed by COPD, and to define novel molecular subclasses of COPD that may contribute to the clinical diversity of the disease. Patterns of airway gene expression will be linked to longitudinal decline in lung function, providing a way to identify individuals at risk for rapid disease progression and an understanding of the mechanisms responsible for variations in their rate of functional decline. How the expression of COPD-related airway gene-expression profiles change during disease progression within lung tissue will elucidate dynamic disease-related processes. The reversibility of these gene expression changes upon treatment with various existing and novel COPD drugs will determine whether airway gene expression signatures can serve as an intermediate marker for evaluating COPD treatments. Finally, the identification of heritable genetic variants that influence the underlying pathways that are responsible for COPD-specific gene expression changes, and testing their ability to identify individuals at risk for COPD, will result in genetic markers of disease susceptibility and progression. The proposed work applies powerful whole-genome exon level and microRNA expression platforms and a variety of novel computational methodologies to samples from a series of large, unique, and well-characterized existing cohorts, and will result in an unprecedented and detailed view of the molecular processes that contribute to COPD pathogenesis. (End of Abstract)